Many forms of cancer, including breast cancer, are dependent on angiogenesis, the growth of blood vessels. There is a great medical need for the development of a safe, effective, and inexpensive means of antiangiogenic therapy. One promising approach is the use of antiangiogenic peptides as the active agents. We have identified novel peptides derived from several classes of proteins that are effective at preventing angiogenesis in our preliminary studies. We have also identified other peptides able to inhibit cancer through additional mechanisms including antilymphangiogenesis and apoptosis. However, in their current form, all of these peptides have a short in vivo half-life and they are not suitable for systemic administration or for long-term action. Thus, there is a need to package, protect, and deliver these peptides in a more stable, sustained fashion. We seek to create new technology to meet this challenge and hypothesize that combinations of these peptides delivered in an engineered fashion could enable synergistic killing of breast cancer. Building on our experience with drug delivery nanoparticles, we will design an effective array of safe, biodegradable polymers for use in forming peptide-containing nanoparticles (Aim 1). These biomaterials will be used to construct nanoparticles that vary in their biophysical properties and in biological properties including tumor accumulation and peptide release. High-throughput synthesis and screening methodology will be used to select for novel nanoparticle formulations, including antiangiogenic peptide nanoparticles, highly efficient for inhibition of human endothelial cell proliferation and migration, inhibition lymphatic endothelial cell proliferation and migration, and promotion of breast cancer apoptosis. Our preliminary work shows these methods are practical and that we can synthesize new nanobiotechnology that performs superiorly to free unencapsulated peptide. In Aim 2, lead nanoparticles containing lead anti-cancer peptides from the in vitro screens in Aim 1 will then be utilized in vivo. Angiogenesis bioreactors implanted subcutaneously in mice will be used to monitor delivery of antiangiogenic peptides by the nanoparticles. The top-performing antiangiogenic formulation will be combined with other lead anti-cancer peptides and tested in a breast cancer mouse model. We aim to create new bionanotechnology that can safely, effectively, and relatively inexpensively treat breast cancer. PUBLIC HEALTH RELEVANCE: This research aims to create new bionanotechnologies that enable the efficient delivery of novel antiangiogenic, antilymphangiogenic, and pro-apoptotic peptides. The nanoparticles proposed here can facilitate the delivery of these peptides to systemically treat breast cancer.